A progressive hypoproliferative anemia develops in most patients with B lymphocyte neoplasms. The hypoproliferative anemia may be due to abnormal cellular interactions of erythroid progenitor cells (CFU-E, BFU-E) with immune lymphocytes (T cells, T gamma, NK cells, B cells). To test this hypothesis, the effects of immune cells in coculture or depletion experiments on CFU-E or BFU-E growth in vitro was studied in patients with B-cell chronic lymphocytic leukemia (CLL; N = 16), multiple myeloma (MM; N\= 5) or non-Hodgkin's lymphoma (NHL; N = 5) and normal controls. Results of erythroid cultures were also correlated with extent of marrow T suppressor (T gamma, OKTA+) cell infiltration. Results document a severe erythroid production defect in all patients with B-lymphocyte malignancies. The production defect in advanced-stage B-cell CLL is worse than that observed in patients with MM or NHL studied to date and is comparable to erythroid progenitor cell production defects observed in patients with pure erythrocyte aplasia or aplastic anemia. CFU-E numbers are barely detectable in advanced Rai stage CLL or those with CLL and aplasia; however, CFU-E in early Rai stage CLL is still only 25% of controls. The extent of erythroid progenitor cell production defect correlates with the degree of marrow OKT8+ T gamma cell infiltration in CLL. Additional studies have shown that normal marrow CFU-E are suppressed by large granular lymphocytes bearing OKT8+ and/or HNK1+ antigens. Moreover, antithymocyte globulin treatment in vitro and in vivo (in one case) resulted in increased erythroid progenitor cell proliferation in normals and in CLL. Collectively, these studies support the hypothesis that erythroid progenitor production defect in B-cell malignancies may be related in part to marrow infiltration with T suppressor or NK cells. In CLL, the degree of marrow T gamma cell infiltration appears to correlate with severity of erythroid production defects and Rai stage.